Dyslipidemias: Clinical Features & Evaluation

Question 1

Lipids most important to development of atherosclerosis

Answer 1

• LDL and HDL most important lipoproteins in terms of atherosclerosis
  
  • Also involved: remnants, lipoprotein a, VLDL (especially in DM)
• Risk stratifying patients based on LDL-C level has beneficial effects on CVD risk (treat with statins)

Question 2

Determination of LDL cholesterol levels

Answer 2

• Calculate with Friedewald formula
  
  • LDL-C = Total cholesterol - HDL-C - (triglycerides / 5)
• Total cholesterol (TC) = HDL-C + LDL-C + VLDL-C
  
  • TC, HDL-C, triglycerides easily measured
  • When fasting, VLDL-C = triglycerides / 5
    
    • As long as triglycerides are <400mg/dL

Question 3

Secondary causes of hyperlipidemia

Answer 3

• Diets high in saturated and trans fat
• Hypothyroidism
• Nephrotic syndrome
• Obstructive liver disease
• Cyclosporine

Question 4

Individualization of risk for ASCVD (risk factors)

Answer 4

• Age (males > females)
• Caucasian vs. African American
• Higher total cholesterol
• Lower HDL-C
• Current cigarette smoking
• Systolic BP > 140
  
  • Or on antihypertensives
• Diabetes

Question 5

2 causes of increased LDL-C

Answer 5

1. Increased LDL-C production
2. Decreased LDL catabolism

Question 6

Causes of increased VLDL production

Answer 6

• Insulin resistance - most common
  
  • Increases in FFA flux from adipose tissue
• Drugs - protease inhibitors, oral estrogens, nephrotic syndrome, chronic renal failure
• Alcohol
  
  • Enhances fatty acid production from ethanol-derived carbons
• Genetics
  
  • lipoprotein lipase (LPL)
  • Apo A5

Question 7

Causes of decreased lipoprotein catabolism

Answer 7

• Decreases in LPL levels or activity
• Primary defects:
  
  • LPL deficiency
  • apo C2 deficiency (specific apoprotein activator of LPL)
  • glycosylphosphatidylinostitol-anchored high-density lipoprotein-binding protein 1 (binds LPL to endothelium) deficiency
• Familial dysbetalipoproteinemia

Question 8

Polygenic/multifactorial causes of hypertriglyceridemia

Answer 8

• Possible when several disorders of lipoprotein triglyceride synthesis and/or catabolism are simultaneously present AND fat remains in diet
• When triglycerides are >1000mgdl –> additional increase attributable to chylomicrons
• Absolute LPL deficiency or two+ disorders of triglyceride metabolism: fasting triglyceride levels up to 30,000mg/dl

Question 9

Increased Non-HDL-C

Answer 9

• Encompasses all apo-B-100 containing lipoproteins (VLDL, IDL, LDL)
  
  • Non-HDL-Cholesterol = TC - HDL
• Correlate closely with central/visceral obesity
• Strong predictor of ASCVD events/death

Question 10

Causes of increased Non-HDL-C

Answer 10

• Familial dysbetalipoproteinemia (FD, broad beta disease)
  
  • Disturbances in IDL and remnant catabolism
  • Manifest: approximately equivalent increase in both LDL-C and triglycerides
  • Most often occurs due to genetic variation in Apo E
    
    • ApoE2 isoform –> increased risk
  • Defective binding of ApoE2 to hepatic receptors recognizing VLDL/chylomicron remnants

Question 11

Low HDL-C

Answer 11

• Associated with increased risk for ASCVD (high levels protective)
• Explained by many properties of HDL: reverse cholesterol transport, anti-oxidant/anti-inflammatory effects
• Can be secondary to:
  
  • Altered composition (hypertriglyceridemia): ApoA1 level unchanged
  • Reduction in HDL particles: ApoA1 level reduced

Question 12

Genetic causes of low HDL-C

Answer 12

• Male gender
• Mutations in ATP binding cassette 1
  
  • Tangier disease: autosomal co-dominant –> accumulation of cholesterol in peripheral organs (orange tonsils)
  • Familial HDL deficiency: autosomal dominant
• Lecithin:cholesterol acyl transferase (LCAT) deficiency
  
  • Homozygous mutations –> corneal opacities & low HDL
• Familial hypoalphalipoproteinemia: autosomal dominant
  
  • Mutations in ApoA1 gene –> premature ASCVD

Question 13

Acquired causes of low HDL-C

Answer 13

• Diet: Decreased fat (high carbohydrate) intake, obesity
• Drugs: Beta blockers, diuretics, progestins, androgens, protease inhibitors
• Hypertriglyceridemic disorders
• Others: sedentary lifestyle, smoking

Question 14

Development/progression of atherosclerosis

Answer 14

• Altered plasma levels of lipids –> effect on arterial wall
• Atherosclerosis begins as fatty streak –> progresses to more advanced disease (fibrous/calcified plaque or complicated lesion)